Pyrrolidine derivatives as anti-amnesia agents

ABSTRACT

The present invention relates to pyrrolidine derivatives of the formula ##STR1## wherein R 1  and R 2  are defined as herein. The compounds are useful as anti-amnestic agent.

This is a division of application Ser. No. 025,664, filed Mar. 13, 1987, now U.S. Pat. No. 4,880,827.

The present invention relates to pyrrolidine derivatives, and their production and use. More particularly, it relates to pyrrolidine derivatives which have inhibitory action for proline-specific endopeptidase and are useful as anti-amnestic agents.

It is well known that vasopressin plays an important role in the memory process and that the administration of vasopressin exhibits excellent therapeutic effects in the treatment of dementia. [Science, 211, P. 601-603 (1981), Brain Research, 157, P. 414-417 (1978)]

However, vasopressin is easily metabolized in the brain by proline-specific endopeptidase. [Journal of Biochemistry, 94, p. 1179-1190 (1983)].

Thus, the inhibitor of proline-specific endopeptidase is expected to increase the content of vasopressin in the brain and to be useful for the treatment of dementia.

It is reported about proline-specific endopeptidase inhibitory agents, for instance N-benzyloxycarbonylglycyl-L-prolylchloromethane and N-benzyloxycarbonyl-L-prolylprolinal [Biochemistry, 16, P. 2942-2948 (1977), Journal of Neurochemistry, 41, P. 69-75 (1983)]. In addition it is known that such proline-specific endopeptidase inhibitors are useful for anti-amnestic agent [Japan Koukai 60-172929, 60-188317, 61-37764, 61-183297, 61-238775, 61-238776, 61-238799.]

We have been studying many kinds of pyrrolidine derivatives and found that pyrrolidine derivatives of the invention have excellent inhibitory activity of proline-specific endopeptidase and also have strong effects on the model of assay of the anti-amnestic action.

Said pyrrolidine derivatives are represented by the formula: ##STR2## wherein R¹ is ##STR3## R² is ##STR4## R³, R⁴, and R⁵ are each independently hydrogen or hydroxy group or halogen or lower alkyl, phenyl, substituted phenyl, --CH₂ R¹⁴, --X--R¹⁵, ##STR5## --NH₂, --NHR¹⁷ or ##STR6## (in which R¹⁴ is phenyl or substituted phenyl. X is oxygen atom or sulfur atom. R¹⁵ is lower alkyl, phenyl, substituted phenyl or --CH₂ R²⁰ (in which R²⁰ is phenyl or substituted phenyl) R¹⁶ is lower alkyl, phenyl, substituted phenyl or --CH₂ R²¹ (in which R²¹ is phenyl or substituted phenyl). R¹⁷ is lower alkyl, five or six-membered cycloalkyl, phenyl, substituted phenyl, --CH₂ R²² (in which R²² is phenyl or substituted phenyl) or ##STR7## in which R²³ is lower alkyl or phenyl or substituted phenyl). R¹⁸ and R¹⁹ are each independently lower alkyl or --CH₂ R²⁴ (in which R²⁴ is phenyl, substituted phenyl)). R⁶ is hydrogen or lower alkyl. R⁷ is hydrogen, lower alkyl, benzyl, ##STR8## or --(CH₂)_(n) --R²⁵ (in which n is an integer of 0 to 4. R²⁵ is --OH, --SH, --NH₂, --SCH₃, ##STR9## --CONH₂, ##STR10## heterocyclic group, or --CO₂ R²⁶ (in which R²⁶ is hydrogen, lower alkyl or benzyl)). R⁸ is hydrogen or, when R⁸ and R⁷ are taken together with the adjacent nitrogen atom and carbon atom to which they are attached, they represent five-membered heterocyclic group. R⁹ is hydrogen, lower alkyl, phenyl or substituted phenyl. R¹⁰ is hydrogen, lower alkyl, lower alkoxy or halogen. m is an integer of 0 to 3. R¹¹ is hydrogen, lower alkyl, phenyl, substituted phenyl or --CH₂ R²⁷ (in which R²⁷ is phenyl or substituted phenyl). R¹² is lower alkyl or, when R¹² and R¹² are each taken together, they represent lower alkylene. R¹³ is lower alkyl, phenyl, substituted phenyl or --CH₂ R²⁸ (in which R²⁸ is phenyl or substituted phenyl).

Among the above-mentioned compounds, examples of preferable ones are compounds wherein R¹ is ##STR11## and R² is ##STR12## (R¹¹ is lower alkyl) ##STR13##

Examples of more preferable ones are compounds wherein R¹ is ##STR14## and R² is ##STR15## (R¹¹ is lower alkyl).

Examples of furthermore preferable ones are compounds wherein R¹ is ##STR16## R² is ##STR17## (R¹¹ is lower alkyl).

In the significances as defined above, the term "substituted phenyl" means phenyl having halogen, lower alkyl or lower alkoxy. The term "halogen" includes fluorine, chlorine, bromine, and iodine. The term "lower alkoxy" is intended to means a straight or branched chain alkoxy group having 1 to 4 carbon atoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy etc.). The term "lower alkyl" is intended to mean a straight or branched chain alkyl group having 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl etc.). The term "lower alkylene" means a straight chain alkylene group having 2 to 3 carbon atoms (e.g. ethylene, triethylene). The term "heterocyclic group" includes mono- or bicyclic heterocyclic group having at least one of nitrogen atom and 3-8 carbon atoms (e.g. imidazole, indole etc.). Five-membered heterocyclic group represent pyrrolidine etc.

Pyrrolidine derivatives (I) inhibit the action of proline-specific endopeptidase which is thought to be main metabolic enzymes for vasopressin and show an excellent effect on the model of assay of the anti-amnestic action. ##STR18##

According to the present invention, the pyrrolidine derivatives (I) are obtainable, for instance, by the following synthetic route.

(1) The first route ##STR19## Wherein R⁶, R⁹, R¹⁰, m, and R¹³ are each as defined above. Y is chlorine, bromine or iodine. R²⁹ ##STR20## R³⁰, R³¹, and R³² are each independently hydrogen, halogen, hydroxy group, lower alkyl, phenyl, substituted pnenyl, ##STR21## in which X, R¹⁴, R¹⁵, R¹⁶, R¹⁸, R¹⁹, and R²³ are each as defined above. R³⁵ is ##STR22## R³⁶ is lower alkyl, five or six-membered cycloalkyl, phenyl, substituted phenyl or --CH₂ R²² (in which R²² is as defined above.). R³³ is hydrogen, lower alkyl, Benzyl, ##STR23## or --(CH₂)_(n) -R³⁸. (in which R³⁷ is lower alkyl, benzyl or phenyl. n is as defined above. R³⁸ is ##STR24## (in which R³⁹ is lower alkyl, benzyl or phenyl. A is oxygen atom or sulfur atom), ##STR25## (in which Z' is chlorine or bromine), --CO₂ R⁴⁰ (in which R⁴⁰ is lower alkyl or benzyl) or heterocyclic group). R³⁴ is hydrogen or, when R³⁴ and R³³ are taken together with adjacent nitrogen atom and carbon atom which they are attached, they represent five-membered heterocyclic group. A synthetic method of aldehyde compound (IV) production is known. [A. Ito et al Chem. Pharm. Bull., 23, P.3081-3087 (1975)]. The conversion of the compound (IV) into compound (VI) can be acomplished by the reaction of the former with a Grignard reagent of the formula: R¹³ MgY (V) in ethers (e.g. ethyl ether, tetrahydrofuran etc.) at a temperature ranging from room temperature to 50° C. Grignard reagent can be prepared by general method. Deprotection of the compound (VI) can be carried out using a catalyst (e.g. 5% Pd-c) for hydrogenolysis in alcohols (e.g. methanol, ethanol, etc.) at room temperature and atmospheric pressure or using excess thioanisol in trifluoroacetic acid [Y. Kiso et al Peptido Chemistry, P.193 (1979)].

The compound (XII) can be obtainable by reacting the compound (VII) with carboxylic acids (e.g. compound (VIII) or (IX) or (X) or (XI) or (XXVI)) in the presence of condensing a agent and reaction stimulator. If necessary, tertiary amine (triethylamine) may be added. An example of the condensing agent is dicyclohexylcarbodiimide or 1-ethyl -3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter this compound is abbreviated to WSC) etc. The reaction stimulator is 1-hydroxybenzotriazole (hereinafter this compound is abbreviated to HOBt), N-hydroxy-5-norbornen-2,3-dicarboxyimide (hereinafter this compound is abbreviated to HONB) or N-hydroxysucciimide (hereinafter this compound is abbreviated to HOSu) etc. The reaction solvent is ethers (e.g. tetrahydrofuran etc.), halogenated hydrocarbons (e.g. chloroform or dichloromethane etc.) N,N-dimethylformamide etc. The reaction is conducted at a preferable temperature from -20° C. to room temperature.

When there is possibility of racemization in the condensation reactions, it is preferable that the reaction is conducted at low temperature (e.g. -10° C.--20° C.) in the beginning early of the reaction and the reaction mixture is warmed slowly to room temperature.

The subsequent deprotection or hydrolysis of the compound (XII) to the compound (I) can be carried out by a per se conventional procedure.

(2) The Secone Route ##STR26## Wherein R⁴¹ is lower alkyl or benzyl. Q is hydroxy group or chlorine or bromine. ##STR27## (in which R⁴⁴, R⁴⁵, and R⁴⁶ are each independently hydrogen, lower alkyl, lower alkoxy or halogen). R⁴³ is lower alkyl.

The compound (XIV) can be obtained by reacting the compound (XIII) with acid halide (R⁴² -Cl or R⁴² -Br) under ice-cooling in an inert solvent. It is preferable to use an acid-accepting agent such as an organic or inorganic base (e.g. alkali hydroxide, alkali carbonate, tertiary-amine, etc.) in the reaction. The inert solvent is water or ethers (e.g. tetrahydrofuran etc.). Of course the compound (XIV) can be obtainable by reacting the compound (XIII) with carboxylic acid (R⁴² -OH) in the presence of condensing agent (e.g. WSC etc.) and reaction stimulator (e.g. HOBt etc.) in the same manner as in the first route.

The compound (XV) can be obtained by reacting the compound (XIV) with methyl methylsulfinylmethyl sulfide in the presence of the base in an inert solvent at a temperature ranging from -20° C. to room temperature. The example of the base is alkali metal hydride or alkali metal t-butoxide. The inert solvent is ethers (e.g. 1,2-dimethoxyethane, tetrahydrofuran etc.). Generally the base and methyl methylsulfinylmethyl sulfide are used more than twice molar of the compound (XIV). The conversion of the compound (XV) into the compound (XVI) can be accomplished by using cupric chloride dihydrate or cupric chloride anhydrous in alcohols (e.g. methanol, ethanol etc.). The amount of cupric chloride used is equivalent to or more in moles to that of the compound (XV). Reduction of the compound (XVI) is carried out using sodium borohydride in alcohols (e.g. methanol, ethanol etc.) at a temperature ranging from -20° C. to room temperature.

(3) THE THIRD ROUTE ##STR28## (in which R¹¹ and R²⁹ are each as defined above).

Compounds (XIX), (XX), (XXI), and (XXII) are prepared in the same manner as the procedure described in Japan Kokai 54-61151.

Esterification of the compound (XXII) can be conducted by reacting the compound (XXII) with alcohols (R¹¹ -OH: e.g. ethanol, methanol etc.) in the presence of thionyl chloride at a temperature ranging from -10° C. to -20° C.

The compound (XXIV) is prepared in the same manner as the procedure described in the first route.

The oxidation is carried out in the same manner as the procedure described in [Synthesis 165-185 (1981)]. For example the oxidation is conducted using dimethylsulfoxide (hereinafter this compound is abbreviated to DMSO), base (e.g. triethylamine etc.), and oxalyl chloride or trifluoroacetic acid anhydride. When the reaction is carried out using DMSO, triethylamine and oxalyl chloride in an inert solvent, a temperature ranging from -60°˜-50° C. is favorable. The inert solvent is dichloromethane etc. Oxalyl chloride needs to be used more than twice molar of the compound (XXIV). The subsequent deprotection or hydrolysis of the compound (XXIV) or (XXV) to the compound (I) can be carried out by a per se conventional procedure.

(4) THE FOURTH ROUTE ##STR29## Wherein Z is ##STR30## R¹² and R²⁹ are each as defined above.

The conversion of the compound (IV) into the compound (XXVII) can be accomplished by using orthoformates (e.g. triethyl orthoformate trimethyl orthoformate etc.), p-toluenesulfonic acid and alcohols (e.g. methanol, ethanol, ethylene glycol etc.). The compound (XXVIII) or (XXIX) is prepared in the same manner as in the first route. The subsequent deprotection or hydrolysis of the compound (XXIX) to the compound (I) may be carried out by a per se conventional procedure for deprotection or hydrolysis as occasion demands.

The pyrrolidine derivatives (I) as well as their acid addition salts can be administered orally or parenterally in the form of conventional pharmaceutical preparations. For instance, they can be administered orally in the form of conventional solid pharmaceutical preparations such as tablets, capsules, syrups and suspensions. Alternatively, they can be administered parenterally by injection in the form of conventional liquid pharmaceutical preparations such as solutions, emulsions, suspensions, etc. Also, they may be directly applied to the rectum in the form of a suppository. Further, the preparations may contain physiologically acceptable carriers, excipients, activators, binding agents, stabilizers, etc. In the case of injections, physiologically acceptable buffers, solubilizing agents or isotonic agents may be incorporated therein. The daily dosage may vary depending upon the symptoms of disease, the age and body weight of the patient, the administration route, etc., and the normal dosage to a human adult is between 1 mg and 1000 mg, preferably between 5 mg and 500 mg dividing in one to several times per day.

Following compounds are obtainable by the present inventions.

1. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S)-1-hydroxyethyl}pyrrolidine ##STR31## 2. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R)-1-hydroxyethyl}pyrrodidine ##STR32## 3. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S)-1-hydroxy-n-propyl}pyrrolidine ##STR33## 4. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R)-1-hydroxy-n-propyl}pyrrolidine ##STR34## 5. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S)-1-hydroxy-2-methylpropyl}pyrrolidine

6. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R)-1-hydroxy-2-methylpropyl}pyrrolidine

7. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine

8. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine

9. L-1benzoyl-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine ##STR35## 10. L-1-(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine ##STR36## 11. L-1-(L-N-benzyloxycarbonylprolyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine ##STR37## 12. L-1-(L-N-benzyloxycarbonylisoleucyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine ##STR38## 13. L-1-(L-N-benzyloxycarbonylphenylalanyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

14. L-1-(3-benzoylpropionyl)-2-{(R)-1-hydroxy-2-methylpropyl}pyrrolidine

15. L-1-(3-benzoylpropionyl)-2-{(S)-1-hydroxy-2-methylpropyl}pyrrolidine

16. L-1-(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine

17. L-1-(3-benzoylpropionyl)-2-{(R)-1-hydroxy-1-phynylmethyl}pyrrolidine

18. L-1-(3-benzoylpropionyl)-2-{(S)-1-hydroxy-1-phenylmethyl}pyrrolidine

19. Ethyl (R,S)-2-hydroxy-2-(L-1-benzoylpyrrolidin-2-yl)acetate ##STR39## 20. Ethyl 2-oxo-2-(L-1-benzoylpyrrolidin-2-yl)acetate ##STR40## 21. Ethyl (R,S)-2-hydroxy-2-{L-1-(3-benzoylpropionyl)-pyrrolidin-2-yl}acetate ##STR41## 22. Ethyl 2-oxo-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate ##STR42## 23. Ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate ##STR43## 24. Ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate ##STR44## 25. Ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}acetate ##STR45## 26. Ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}acetate ##STR46## 27. Ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylpropyl)pyrrolidin-2-yl}acetate ##STR47## 28. Ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylprolyl)pyrrolidin-2-yl}acetate ##STR48## 29. L-1-(L-N-benzyloxycarbonylvalyl)-2-(1,3-dioxolan-2-yl)pyrrolidine ##STR49## 30. L-1-(L-N-benzyloxycarbonylprolyl)-2-(1,3-dioxolan-2-yl)pyrrolidine ##STR50## 31. Ethyl (R,S)-2-hydroxy-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}acetate ##STR51## 32. Ethyl 2-oxo-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}acetate ##STR52## 33. Ethyl (R,S)-2-hydroxy-2-{L-1-(4-hydroxybenzoyl)pyrrolidin-2-yl}acetate ##STR53## 34. Ethyl 2-oxo-2-{L-1(4-hydroxybenzoyl)pyrrolidin-2-yl}acetate ##STR54## 35. Ethyl (R,S -2-hydroxy-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate ##STR55## 36. Ethyl 2-oxo-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate ##STR56## 37. Ethyl (R,S)-2-hydroxy-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate ##STR57## 38. Ethyl 2-oxo-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate ##STR58## 39. Ethyl (R,S)-2-hydroxy-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate ##STR59## 40. Ethyl 2-oxo-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate ##STR60## 41. Ethyl (R,S)-2-hydroxy-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate ##STR61## 42. Ethyl 2-oxo-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate ##STR62## 43. Ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-n-butoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate ##STR63## 44. Ethyl 2-oxo-2-[L-1-{3-(4-n-butoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate ##STR64## 45. Ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acetate ##STR65## 46. Ethyl 2-oxo-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acetate ##STR66## 47. Ethyl (R,S)-2-hydroxy-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate ##STR67## 48. Ethyl 2-oxo-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin2-yl}acetate ##STR68## 49. Ethyl (R,S)-2-hydroxy-2-[L-1-{3-(2,5-dimethoxybenzoyl) propionyl}pyrrolidin-2-yl]acetate ##STR69## 50. Ethyl 2-oxo-2-[L-1-{3-(2,5-dimethoxybenzoyl) propionylpyrrolidin-2-yl}acetate

Practical and presently preferred embodiments of the invention are illustratively shown in the following Reference Examples or Examples, which are not intended to limit the scope of the invention thereto.

REFERENCE EXAMPLE 1 Preparation of L-1-benzyloxycarbonyl-2-{(R,S)-1-hydroxyethyl}pyrrolidine

Magnesium (0.2 g, 8.6 mmol) and iodine (catalytic amount) were added to ether (10 ml). To this suspension was added dropwise an ether (3 ml) solution of methyl iodide (1.8 g, 12.7 mmol) at the rate of gently reflux under a nitrogen atomosphere. After 20 minutes an ether (10 ml) solution of L-N-benzyloxycarbonyl-2-formylpyrrolidine (2.0 g, 8.6 mmol) was added dropwise to the reaction mixture, followed by stirring for 2 hours. A coldsaturated aqueous ammonium chloride solution was added dropwise to the reaction mixture with ice-cooling. The mixture was extracted with ether. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave an oil, which was subjected to column chromatography on silica gel. Elution with n-hexane: ethyl acetate=1:1 gave two products which have different R_(f) value each other. The NMR spectra data of the two products were showed. One product has higher R_(f) value, L-1-benzyloxycarbonyl-2-{(R) or (S)-1-hydroxyethyl}pyrrolidine

NMR(CDCl₃)δ: 1.13 (3H, d, J=8 Hz), 1.50-2.30 (4H, m), 3.20-4.20 (4H, m), 5.10 (2H, S), 7.33 (5H, S)

The other product which has lower R_(f) value, L-1-benzyloxycarbonyyl-2-{(S) or (R) -1-hydroxyethyl}pyrrolidine

NMR(CDCl₃)δ: 1.17 (3H, d, J=5 Hz), 1.50-2.20 (4H, m), 3.20-4.20 (4H, m), 5.10 (2H, S), 7.32 (5H, S)

The following compounds were prepared in the same manner as in Reference Example 1. The NMR spectra data of the compounds were described.

(a) L-1-Benzyloxycarbonyl-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

NMR(CDCl₃)δ: 0.96 (3H, t, J=7 Hz), 1.20-2.20 (6H, m), 3.10-4.10 (4H, m), 4.60 (1H, S), 5.10 (2H, S), 7.30 (5H, S)

(b) L-1-Benzyloxycarbonyl-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine

NMR(CDCl₃)δ: 0.80-2.30 (11H, m), 3.20-4.10 (4H, m), 5.10 (2H, S), 7.30 (5H, S)

(c)-1

L-1-Benzyloxycarbonyl-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine (this compound has higher R_(f) value in the two products)

NMR(CDCl₃)δ: 0.90 (3H, d, J=6 Hz), 1.00 (3H, d, J=6 Hz), 1.50-2.20 (4H, m), 3.20-4.30 (5H, m), 5.10 (2H, S), 7.33 (5H, S)

(c)-2

L-1-Benzyloxycarbonyl-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine (this compound has lower R_(f) value in the two products)

NMR(CDCl₃)δ: 0.90 (3H, d, J=6 Hz), 1.00 (3H, d, J=6 Hz), 1.50-2.50 (4H, m), 3.20 4.50 (4H, m), 5.17 (2H, S), 7.34 (5H, S)

(d) L-1-Benzyloxycarbonyl-2-{(R,S)-1-hydroxy-1-pheylmethyl}pyrrolidine

NMR(CDCl₃)δ: 1.30-2.20 (4H, m), 3.00-3.80 2H, m), 4.00-4.50 (1H,m), 4.50-4.80 (1H, m), 5.20 (2H, S), 7.10-7.60 (10H, m)

REFERENCE EXAMPLE 2 Preparation of L-2-{(R) or (S)-1-hydroxyethyl}pyrrolidine

L-1-Benzyloxycarbonyl-2-{(R) or (S)-1-hydroxyethyl}pyrrolidine (1.2 g, 4.9 mmol) (this compound was obtained in the Reference Example 1 and has higher R_(f) valure in the two products) and thioanisole (24.3 g, 196.0 mmol) was added to trifluoroacetic acid (70 ml), followed by stirring for 2 hours at room temperature. After removal of trifluoroacetic acid by distillation under the reduced pressure, benzene (100 ml) was added to theresidue. Benzene was evaporated under reduced pressure, the residue was shaked with n-hexane (100 ml) and n-hexane layer was removed. This operation was repeated 3 times, and title compound was obtained.

REFERENCE EXAMPLE 3 Preparation of L-2-{(S) or (R)-1-hydroxyethyl}-pyrrolidine

L-1-Benzyloxycarboxyl-2-{(S) or (R)-1-hydroxyethyl}pyrrolidine (1.2 g, 4.9 mmol) (this compound was obtained in Reference Example 1 and has lower R_(f) value in the two products) and thioanisole (24.3 g, 196 mmol) werereacted in trifluoroacetic acid (70 ml) in the same manner as in Reference Example 2, there was obtained L-2-{(S) or (R)-1-hydroxyethyl}pyrrolidine.

REFERENCE EXAMPLE 4 Preparation of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

5% Pd-C (1.5 g) was added to a methanol (30 ml) solution of L-1-benzyloxycarbonyl-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.5 g, 5.7 mmol). Hydrogenolysis is carried out at room temperature and atmospheric pressure.

REFERENCE EXAMPLE 5 Preparation of L-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine

In the same manner as in Reference Example 4 but using L-1-benzyloxycarbonyl-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine (this compound was obtained in Reference Example 1-(C)-1) as the starting materials, there was obtained L-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine.

REFERENCE EXAMPLE 6 Preparation of L-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine

In the same manner as in Reference Example 4 but using L-1-benzyloxycarbonyl-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine (this compound was obtained in Reference Example 1-(C)-2) as the starting materials, there was obtained L-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine.

REFERENCE EXAMPLE 7 Preparation of L-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine

In the same manner as in Reference Example 4 but using L-1-benzyloxycarbonyl-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine as the starting materials, there was obtained L-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine.

REFERENCE EXAMPLE 8 Preparation of L-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine

In the same manner as in Reference Example 4 but using L-1-benzyloxycarbonyl-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine as thestarting materials, there was obtained L-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine.

REFERENCE EXAMPLE 9 Preparation of methyl L-1-benzoylprolinate

Methyl L-prolinate hydrogen chloride (10.0 g, 60 mmol) was added to an aqueous sodium hydrogen carbonate (11 g) solution. Benzoyl chloride (8.5 g, 60 mmol) was added dropwise to the reaction mixture with ice-cooling, followed by stirring for five hours. The reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Evaporation of ethyl acetate gave methyl L-1-benzoylprolinate.

NMR(DMSO-d₆)δ: 1.70-2.50 (4H, m), 3.20-3.90 (5H, m), 4.20-4.63 (1H, m), 7.43 (5H, s)

REFERENCE EXAMPLE 10 Preparation of ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride

Thionyl chloride (0.78 g, 6.6 mmol) was added dropwise to ethanol below -15° C. (R,S)-2-Hydroxy-2-(L-pyrrolidin-2-yl)acetic acid (0.95 g, 6.6 mmol) was added to the reaction mixture, followed by stirring for 30 minutes below -15° C. and overnight at room temperature. Evaporation of ethanol gave ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride.

NMR(CD₃ OD-CDCl₃)δ: 1.30 (3H, t, J=7 Hz), 1.70-2.50 (4H, m), 3.20-3.60 (2H, m), 3.65-4.60 (4H, m).

REFERENCE EXAMPLE 11 Preparation of L-1-benzyloxycarbonyl-2-(1,3-dioxolan-2-yl)pyrrolidine

A benzene (100 ml) solution of L-1-benzyloxycarbonyl-2-formylpyrrolidine (4.7 g), triethyl orthoformate, and p-toluenesulfonic acid (0.5 g) was heated under reflux for 0.5 hr. When the reaction was carried out, the flask was attached to a water separator. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with benzene. The extract was washed with water, dried over anhydrous magnesiumsulfate. Evaporation of benzene gave L-1-benzoylcarbonyl-2-(1,3-dioxolan-2-yl)pyrrolidine.

NMR(CDCl₃)δ: 1.60-2.20 (4H, m), 3.30-4.40 (8H, m), 5.15 (2H, s),7.37 (5H, s).

REFERENCE EXAMPLE 12 Preparation of L-(1,3-dioxolan-2-yl)pyrrolidine

In the same manner as in Reference Example 4 but using L-1-benzyloxycarbonyl-2-(1,3-dioxolan-2-yl)pyrrolidin as the starting materials, there was obtained L-(1,3-dioxolan-2-yl)pyrrolidine.

EXAMPLE 1 Preparation of L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R) or (S)-1-hydroxy-n-propyl}pyrrolidine

HOBt (0.8 g, 5.9 mmol) and L-N-benzyloxyvaline (1.45 g, 5.9 mmol) was addedto chloroform (50 ml) and cooled to -10° C.˜-20° C. To this mixture were added L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (0.82 g,5.9 mmol), triethylamine (1 ml), and WSC (1.1 g, 5.9 mmol), followed by stirring for 2 hours at -10° C.˜-20° C. and overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with chloroform. The extract was washed successively with anaqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave an oil, which was subjected to column chromatography on silica gel. The column was developed with 0.5 l of n-hexane: ethyl acetate=2:1 and successively with 0.5 l of n-hexane: ethyl acetate=1:1. Elution with ethyl acetate gave two products which have different R_(f) value each other.

The NMR spectra data of the two products were showed.

One product which has higher R_(f) value, L-1-(L-N-benzyloxycarbonylvalyl)-2- (R) or (S) -1-hydroxy-n-propyl}pyrrolidine.

NMR(CDCl₃)δ: 0.80-2.30 (16H, m), 3.20-4.60 (6H, m), 5.07 (2H, s), 5.60-6.90 (1H, br), 7.30 (5H, s)

The other product which has lower R_(f) value, L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S) or (R) -1-hydroxy-n-propyl}pyrrolidine.

NMR(CDCl₃)δ: 0.80-2.30 (16H, m), 3.20-4.50 (6H, m), 5.08 (2H, s), 5.50-5.80 (1H, br), 7.33 (5H, s)

EXAMPLE 2 Preparation of L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R) or (S)-1-hydroxyethyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R) or (S)-1-hydroxyethyl}pyrrolidine (0.6 g, 4.8 mmol) which was prepared in Reference Example 2, L-N-benzyloxycarbonylvaline (1.20 g, 4.8 mmol), HOBt (0.65 g, 4.8 mmol), triethylamine (1 ml), and WSC (0.92 g, 4.8 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R) or (S)-1-hydroxyethyl}pyrrolidine.

NMR(CDCl₃)δ: 0.80-1.35 (9H, m), 1.35-0.20 (5H, m), 3.15-4.60 (5H, m), 5.07 (2H, s), 5.40-5.80 (2H, br), 7.33 (5H, s)

EXAMPLE 3 Preparation of L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S) or (R)-1-hydroxyethyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(S) or (R)-1-hydroxyethyl}pyrrolidine (0.60 g, 4.8 mmol) which was prepared in Reference Example 3, L-N-benzyloxycarbonylvaline (1.20 g, 4.8 mmol), HOBt (0.65 g, 4.8 mmol), triethylamine (1 ml), and WSC (0.92 g, 4.8 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S) or (R)-1-hydroxyethyl}pyrrolidine.

NMR(CDCl₃)δ: 0.80-1.35 (9H, m), 1.40-2.30 (5H, m), 3.20-4.90 (6H, m), 5.07 (2H, s), 6.03 (1H, d, J=10 Hz), 7.32 (5H, s)

EXAMPLE 4 Preparation of L-1-benzoyl-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.25 g, 8.9 mmol), benzoic acid(1.10 g, 8.9 mmol), triethylamine (1 ml), HOBt (1.20 g, 8.9 mmol), and WSC (1.70 g, 8.9 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1-benzoyl-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

NMR(CDCl₃)δ: 1.05 (3H, t, J=6 Hz), 1.20-2.25 (6H, m), 3.40-3.70 (2H, m), 4.00-4.60 (2H, m), 7.43 (5H, s)

EXAMPLE 5 Preparation of L-1-(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.25 g, 8.9 mmol), 3-benzoylpropionic acid (1.60 g, 8.9 mmol), HOBt (1.20 g, 8.9 mmol), triethylamine (1 ml), and WSC (1.70 g, 8.9 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1-(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-propyl}-pyrrolidine.

NMR(CDCl₃)δ: 1.00 (3H, t, J=6 Hz), 1.50-1.80 (2H, m), 1.80-2.20 (4H, m), 2.60-2.90 (2H, m), 3.30-3.80 (5H, m), 4.00-4.30 (1H, m), 4.73 (1H, d, J=5 Hz), 7.30-7.70 (3H, m), 7.95-8.10 (2H, m)

EXAMPLE 6 Preparation of L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine (1.00 g, 7.0 mmol) which was prepared in Reference Example 5, L-N-benzyloxycarbonylvaline (1.74 g, 7.0 mmol), HOBt (1.00 g, 7.0 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.0mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine.

NMR(CDCl₃) δ: 0.87-1.20 (9H, m), 1.40-2.27 (6H, m), 3.20-4.13 (3H, m), 4.13-4.57 (3H, m), 5.12 (2H, s), 5.40-5.67 (1H, m), 7.37 (5H, s)

EXAMPLE 7 Preparation of L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine (0.50 g, 3.5 mmol) which was prepared in Example 1, L-N-benzyloxycarbonylvaline (0.87 g, 3.5 mmol), HOBt (0.50 g, 3.5 mmol), triethylamine (1 ml), and WSC (0.70 g, 3.5 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine.

NMR(CDCl₃)δ: 0.77-1.20 (9H, m), 1.40-2.60 (6H, m), 3.23-4.00 (3H, m), 4.20-4.67 (3H, m), 5.10 (2H, s), 5.50-5.90 (1H, m), 7.33 (5H, s)

EXAMPLE 8 Preparation of L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine (1.00 g, 7.0 mmol), L-N-benzyloxycarbonylvaline (1.75 g, 7.0 mmol), HOBt (0.94 g, 7.0 mmol), triethylamine (1 ml), and WSC (1.34 g, 7.0 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine.

NMR(CDCl₃)δ: 0.85-2.15 (5H, m), 1.20-1.70 (4H, m), 1.70-2.15 (5H, m), 3.30-4.00 (4H, m), 4.00-4.60 (2H, m), 5.09 (2H, s), 5.57 (1H, br), 7.35 (5H, s)

EXAMPLE 9 Preparation of L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine (0.85 g, 4.8 mmol), L-N-benzyloxycarbonylvaline (1.20 g, 4.8 mmol), HOBt (0.65 g, 4.8 mmol), triethylamine (0.7 ml), and WSC (0.92 g, 4.8 mmol) was stirred for 2 hoursat -10° C.˜-20° C. and overnight at room temperature togive L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine.

NMR(CDCl₃)δ: 1.04 (6H, t, J=6 Hz), 1.40-2.20 (5H, m), 3.40-4.00 (2H, m), 4.20-4.60 (2H, m), 5.08 (2H, s), 5.57 (1H, d, J=9 Hz), 7.33 (10H,s)

EXAMPLE 10 Preparation of L-1-(L-N-benzyloxycarbonylpropyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.00 g, 7.2 mmol), L-N-benzyloxycarbonylproline (1.80 g, 7.2 mmol), HOBt (1.00 g, 7.2 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.2 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylpropyl)-2-{(R,S)-1-hydroxy-npropyl}pyrrolidine.

NMR(CDCl₃)δ: 0.80-2.43 (13H, m), 3.17-4.77 (8H, m), 4.80-5.27 (2H, m), 7.33 (5H, s)

EXAMPLE 11 Preparation of L-1-(L-N-benzyloxycarbonylisoleucyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.00 g, 7.2 mmol), L-N-benzyloxycarbonylisoleucine (1.90 g, 7.2 mmol), HOBt (1.00 g, 7.2 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.2 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylisoleucyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine.

NMR(CDCl₃)δ: 0.80-2.20 (14H, m), 3.27-3.67 (2H, m), 3.67-4.07 (1H, m), 4.07-4.57 (2H, m), 5.07 (2H, s), 5.63 (1H, d, J=9 Hz), 7.33 (5H, s)

EXAMPLE 12 Preparation of L-1-(L-N-benzyloxycarbonylphenylalanyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.00 g, 7.2 mmol), L-N-benzyloxycarbonylphenylalanine (2.20 g, 7.2 mmol), HOBt (1.00 g, 7.2 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.2 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylphenylalanyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine.

NMR(CDCl₃)δ: 0.80-1.90 (9H, m), 2.50-3.90 (5H, m), 3.93-4.57 (1H, m), 4.57-4.97 (1H, m), 5.07 (2H, s), 5.80 (1H, d, J=9 Hz), 7.30 (5H, s), 7.35 (5H, s)

EXAMPLE 13 Preparation of L-1-(3-benzoylpropionyl)-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine (1.00 g, 7.0 mmol) which was prepared in Reference Example 5, 3-benzoylpropionic acid (1.24 g, 7.0 mmol), HOBt (1.00 g, 7.0 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.0mmol) was stirred for 2 hours at -10° C.˜ -20° C. and overnight at room temperature to give L-1-(3-benzoylpropionyl)-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine

NMR(CDCl₃)δ: 0.67-1.30 (6H, m), 1.40-2.23 (5H, m), 2.40-2.93 (2H, m), 2.93-3.90 (4H, m), 4.10-4.40 (1H, m), 4.75 (1H, d, J=5 Hz), 7.20-7.77 (3H, m), 7.93-8.27 (2H, m)

EXAMPLE 14 Preparation of L-1-(3-benzoylpropionyl)-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine (1.00 g, 7.0 mmol) which was prepared in Reference Example 6, 3-benzoylpropionic acid (1.24 g, 7.0 mmol), HOBt (1.00 g, 7.0 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.0mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1(3-benzoylpropionyl)-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine.

NMR(CDCl₃)δ: 0.73-1.15 (6H, m), 1.43-2.43 (5H, m), 2.43-3.00 (2H, m), 3.20-4.00 (4H, m), 4.00-4.70 (2H, m), 7.27-7.67 (3H, m), 7.90-8.15 (2H, m)

EXAMPLE 15 Preparation of L-1-(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine (1.15 g, 8.0 mmol), 3-benzoylpropionic acid (1.43 g, 8.0 mmol), HOBt (1.10 g, 8.0 mmol), triethylamine (1 ml), and WSC (1.53 g, 8.0 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give L-1(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine.

NMR(CDCl₃)δ: 0.70-2.33 (11H, m), 2.50-2.93 (2H, m), 3.00-4.33 (7H, m), 7.30-7.73 (3H, m), 7.80-8.20 (2H, m)

EXAMPLE 16 Preparation of L-1-(3-benzoylpropionyl)-2-{(R) or (S)-1-hydroxy-1-pehnylmethyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine (0.85 g, 4.8 mmol), 3-benzoylpropionic acid (0.85 g, 4.8 mmol), HOBt (0.65 g, 4.8 mmol), triethylamine (1 ml), and WSC (0.92 g, 4.8 mmol) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature to give two products which have different R_(f) value each other.

The NMR spectra data of the two products were showed. One product which hashigher R_(f) value, L-1-(3-benzoylpropionyl)-2-{(R) or (S)-1-hydroxy-1-phenylmethyl}pyrrolidine.

NMR(CDCl₃)δ: 1.40-2.20 (4H, m), 2.72 (2H, t, J=6 Hz), 3.00-3.70 (4H, m), 4.52 (1H, m), 5.00 (1H, d, J=3 Hz), 5.87 (1H, br), 7.15-7.65 (8H,m), 7.80-8.20 (2H, m)

The other product which has lower R_(f) value, L-1-(3-benzoylpropionyl)-2-{(S) or (R)-1-hydroxy-1-phenylmethyl}pyrrolidine.

NMR(CDCl₃)δ: 1.50-2.10 (4H, m), 2.70-2.90 (2H, m), 3.30-3.80 (4H, m), 4.60-4.70 (2H, m), 5.45 (1H, br), 7.20-7.60 (8H, m), 7.90-8.10 (2H, m)

EXAMPLE 17 Preparation of L-1-benzoyl-2-(2-methylthio-2-methylsulfoxyacetyl)pyrrolidine

To a suspension of sodiuum hydride (60% oil dispersion, 0.52 g, 13 mmol) in1,2-dimethoxyethane (15 ml) was added methyl methylsulfinylmethyl sulfide (1.60 g, 13 mmol), followed by stirring for 2 hours at 50° C.-55° C. Methyl L-1-benzoylprolinate (1.00 g, 4.3 mmol) which was prepared in Reference Example 9 was added to the reaction mixture with ice-cooling, followed by stirring overnight at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Evaporation of ethyl acetate gave L-1-benzoyl-2-(2-methylthio-2-methylsulfoxyacetyl)pyrrolidine.

NMR(CDCl₃)δ: 1.70-2.65 (4H, m), 2.22 (3H, s), 2.84 (3H, s), 3.45-3.85 (2H, m), 4.74 (1H, s), 4.75-5.00 (1H, m), 7.30-7.70 (5H, m)

EXAMPLE 18 Preparation of ethyl 2-oxo-2-(L-1-benzoylpyrrolidine-2-yl)acetate

A mixture of L-1-benzoyl-2-(2-methylthio-2-methylsulfoxyacetyl)pyrrolidine (7.00 g, 21.5 mmol) and cupric chloride dihydrate (3.67 g, 21.5 mmol) in ethanol (100 ml) was stirred overnight at room temperature. After removal of ethanol by distillation, the residue was dissolved in ethyl acetate andthe solution was washed with water, dried over anhydrous magnesium sulfate.Evaporation of the solvent gave an oil, which was subject to column chromatography on silica gel. Elution with ethyl acetate gave ethyl 2-oxo-2-(L-1-benzoylpyrrolidin-2-yl)acetate.

NMR(CDCl₃)δ: 1.37 (3H, t, J=7 Hz), 1.70-2.70 (4H, m), 3.50-3.93 (2H, m), 4.35 (2H, q, J=7 Hz), 5.10-5.40 (1H, m), 7.30-7.70 (5H, m)

EXAMPLE 19 Preparation of ethyl (R,S)-2-hydroxy-2-(L-1-benzoylpyrrolidin-2-yl)acetate

To a methanol (30 ml) solution of ethyl 2-oxo-2-(L-1-benzoylpyrrolidin-2-yl)acetate was added gradually sodium borohydrate (13 mg) under ice-cooling, followed by stirring for one hour at room temperature. After removal of methanol by distillation, the residue was dissolved in ethyl acetate and the solvent was washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate. Evaporation of ethyl acetate gave an oil, which was subjected to column chromatography on silica gel. Elution with ethyl acetate gave ethyl(R,S)-2-hydroxy-2-(L-1-benzoylpyrrolidin-2-yl)acetate.

NMR(CDCl₃)δ: 1.35 (3H, t, J=7 Hz), 1.80-2.40 (4H, m), 3.40-3.95 (3H, m), 4.10-4.50 (3H, m), 4.60-4.80 (1H, m), 7.43 (5H, s)

EXAMPLE 20 Preparation of ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate

To a mixture of L-N-benzyloxycarbonylvaline (2.25 g, 9.0 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin2-yl)acetate hydrochloride (1.88 g, 9.0 mmol) which was prepared in Reference Example 10, and HOBt (1.21 g, 9.0 mmol) in chloroform (40 ml) were added triethylamine (3 ml) and WSC (1.72 g, 9.0 mmol) under carbon tetrachloride-dry ice cooling, followed by stirring for 2 hours at the same temperature and overnight at room temperature. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract waswashed with water, dried over anhydrous magnesium sulfate. Evaporation of chloroform to give an oil, which was subjected to column chromatography onsilica gel. Elution with n-hexane: ethyl acetate=1:1 gave ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate.

NMR(CDCl₃)δ:0.97 (6H, t, J=7 Hz), 1.30 (3H, t, J=8 Hz), 1.60-2.30 (5H, m), 3.30-3.95 (3H, m), 4.10-4.60 (4H, m), 4.72 (1H, d, J=2 Hz), 5.08 (2H, s), 5.37-5.70 (1H, br), 7.35 (5H, s)

EXAMPLE 21 Preparation of ethyl (R,S)-2-hydroxy-2-(L-1{L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2yl)acetate hydrochloride (1.00 g, 4.8 mmol) which was prepared in Reference Example 10, L-N-benzyloxycarbonylisoleucine (1.28 g, 4.8 mmol), WSC (0.93 g, 4.8 mmol), HOBt (0.65 g 4.8 mmol), and triethylamine (1.7 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}-acetate.

NMR(CDCl₃)δ: 0.96 (6H, t, J=5 Hz), 1.31 (3H, t, d, J=7 Hz, J=3 Hz), 1.45-2.30 (7H, m), 3.10-4.00 (3H, m), 4.10-4.60 (4H, m), 4.75 (1H, d,J=2 Hz), 5.08 (2H, s), 5.40-5.70 (1H, br), 7.34 (5H, s)

EXAMPLE 22 Preparation of ethyl (R,S)-2-hydroxy-2{L-1-(L-N-benzyloxycarbonylpropyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.00 g, 4.8 mmol) which was prepared in Reference Example 10, L-N-benzyloxycarbonylproline (1.20 g, 4.8 mmol), WSC (0.93 g, 4.8 mmol), HOBt (0.65 g, 4.8 mmol), and triethylamine (1.7 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylprolyl)pyrrolidin-2yl}acetate.

NMR(CDCl₃)δ: 1.25 (3H, t, J=7 Hz), 1.70-2.30 (8H, m), 3.30-3.90 (4H, m), 3.90-4.90 (6H, m), 5.10 (2H, d, J=3 Hz), 7.32 (5H, s)

EXAMPLE 23 Preparation of ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate

To a dichloromethane (5 ml) solution of oxalyl chloride (1.02 g, 8.0 mmol) was added dropwise a dichloromethane (5 ml) solution of DMSO (1.26 g, 16.0mmol) at -50° C.˜-60° C. After 2 minutes, a dichloromethane (10 ml) solution of ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate(1.64 g, 4.0 mmol) was added dropwise to the reaction mixture at -50° C.˜-60° C. After 15 minutes, triethylamine (4.04 g, 40.0 mmol) was added dropwise to the reaction mixture for 5 minutes at the same temperature, followed by stirring for one hour at room temperature. The reaction mixture was poured into water and extracted twice with dichloromethane. After removal of dichloromethane by distillation, the residue was dissolved in ether and the solvent was washed successively with a cold 1% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. Evaporation of ether gave ethyl 2-oxo-2(L-1-{L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate.

NMR(CDCl₃)δ: 0.97 (6H, t, J=7 Hz), 1.36 (3H, t, J=8 Hz), 1.65-2.45 (5H, m), 3.48-3.98 (2H, m), 4.20-4.45 (3H, m), 4.90-5.26 (3H, m), 5.27-5.67 (1H, br), 7.33 (5H, s)

EXAMPLE 24 Preparation of ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}acetate (0.5 g, 1.2 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.14 g, 1.4 mmol), DMSO (0.22 g, 2.8 mmol), and triethylamine (0.71 g, 7.0 mmol) in dichloromethane.

NMR(CDCl₃)δ: 0.94 (6H, t, J=6 Hz), 1.34 (3H, t, J=7 Hz), 1.50-2.30 (7H, m), 3.40-4.00 (2H, m), 4.10-4.50 (3H, m), 4.90-5.20 (3H, m), 5.60 (1H, d, J=9 Hz), 7.30 (5H, s)

EXAMPLE 25 Preparation of ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylpropyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylprolyl)pyrrolidin-2-yl}acetate (0.60 g, 1.5 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylprolyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.44 g, 3.4 mmol), DMSO (0.55 g, 7.0 mmol), and triethylamine (1.77 g, 17.5 mmol) in dichloromethane.

NMR(CDCl₃)δ: 1.37 (3H, t, J=7 Hz), 1.70-2.50 (8H, m), 3.30-4.00 (4H, m), 4.15-4.70 (3H, m), 4.80-5.30 (3H, m), 7.43 (5H, s)

EXAMPLE 26 Preparation of L-1-(L-N-benzyloxycarbonylvalyl)-2-(1,3-dioxolan-2-yl)pyrrolidine

To a mixture of L-(1,3-dioxolan-2-yl)pyrrolidine (1.48 g, 10.3 mmol) which was prepared in Reference Example 12, L-N-benzyloxycarbonylvaline (2.60 g,10.3 mmol), and HOBt (1.50 g, 10.3 mmol) in chloroform under carbon tetrachloride-dry ice cooling were added triethylamine (2 ml) and WSC (2.00 g, 10.3 mmol), followed by stirring for 2 hours at the same temperature and overnight at room temperature. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of chloroform gave an oil, which was subjected to column chromatography onsilica gel. Elution with ethyl acetate gave L-1-(L-N-benzyloxycarbonylvalyl)-2-(1,3-dioxolan-2-yl)pyrrolidine.

NMR(CDCl₃)δ: 0.93 (3H, d, J=6 Hz), 1.00 (3H, d, J=6 Hz), 1.50-2.33 (5H, m), 3.50-5.00 (8H, m), 5.07 (2H, s), 5.07-5.20 (1H, m), 5.33-5.75 (1H, m), 7.33 (5H, s)

EXAMPLE 27 Preparation of L-1-(L-N-benzyloxycarbonylprolyl)-2-(1,3-dioxolan-2-yl)pyrrolidine

In the same manner as in Example 26, a mixture of L-(1,3-dioxolan-2-yl)pyrrolidine (1.48 g, 10.3 mmol), L-N-benzyloxycarbonylproline (2.57 g, 10.3 mmol), HOBt (1.50 g, 10.3 mmol), WSC (2.00 g, 10.3 mmol), and triethylamine (2 ml) was stirred for 2hours at -10° C.˜-20° C. and overnight at room temperature gave L-1-(L-N-benzyloxycarbonylprolyl)-2-(1,3-dioxolan-2-yl)pyrrolidine.

NMR(CDCl₃)δ: 1.40-2.40 (8H, m), 3.23-4.17 (8H, m), 4.20-5.33 (5H, m), 7.33 (5H, s)

EXAMPLE 28 Preparation of ethyl (R,S)-2-hydroxy-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 4-methoxybenzoic acid (1.05 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol), WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gaveethyl (R,S)-2-hydroxy-2-{L-1-(4-methxybenzoyl)pyrrolidin-2-yl}acetate.

NMR(CDCl₃)δ: 1.29 (3H, t, J=7 Hz), 1.63-1.79 (1H, m), 1.90-2.10 (3H, m), 3.46-3.57 (2H, m), 3.84 (3H, s), 4.25 (2H, q, J=7 Hz), 4.49 (1H, d, J=8 Hz), 4.60 (1H, t, J=8 Hz), 4.70 (1H, d, J=7 Hz), 6.89-6.92 (2H, m),7.49-7.53 (2H, m)

EXAMPLE 29 Preparation of ethyl (R,S)-2-hydroxy-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 3,4-dimethoxybenzoic acid(1.26 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate.

NMR(CDCl₃)δ: 1.30 (3H, t, J=7 Hz), 1.65-1.79 (1H, m), 1.91-2.12 (3H, m), 3.48-3.65 (2H, m), 3.90 (3H, s), 3.92 (3H, s), 4.26 (2H, q, J=7 Hz), 4.42 (1H, d, J=7 Hz), 4,57-4.63 (1H, m), 4.72 (1H, d, J=7 Hz), 6.86 (1H, d, J=9Hz), 7.10-7.13 (2H, m)

EXAMPLE 30 Preparation of ethyl (R,S)-2-hydroxy-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 4-methylbenzoic acid (0.94 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate

NMR(CDCl₃)δ: 1.26-1.38 (3H, m), 1.65-1.75 (1H, m), 1.90-2.20 (3H, m), 2.38 (3H, s), 3.47-3.52 (2H, m), 4.26 (2H, q, J=7 Hz), 4.48 (1H, d, J=7 Hz), 4.59 (1H, t, J=8 Hz), 4.70 (1H, d, J=7 Hz), 7.18-7.22 (2H, m),7.39-7.44 (2H, m)

EXAMPLE 31 Preparation of ethyl (R,S)-2-hydroxy-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 3,4,5-trimethoxybenzoic acid (1.46 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate.

NMR(CDCl₃)δ: 1.34 (3H, t, J=7 Hz), 1.65-1.77 (1H, m), 1.90-2.23 (3H, m), 3.23-3.42 (2H, m), 3.85 (3H, s), 3.87 (3H, s), 3.91 (3H, s), 3.97(1H, d, J=7 Hz), 4.17-4.38 (3H, m), 4.62-4.68 (1H, m), 6.66 (1H, d, J=9 Hz), 6.96 (1H, d, J=9 Hz)

EXAMPLE 32 Preparation of ethyl (R,S)-2-hydroxy-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 4-fluorobenzoic acid (0.97 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate

NMR(CDCl₃)δ: 1.30 (3H, t, J=7 Hz), 1.65-2.15 (4H, m), 3.45-3.52 (2H, m), 4.16 (1H, d, J=7 Hz), 4.27 (2H, q, J=7 Hz), 4.57-4.64 (1H, m), 4.74 (1H, d, J=7 Hz), 7.06-7.12 (2H, m), 7.52-7.57 (2H, m)

EXAMPLE 33 Preparation of ethyl (R,S)-2-hydroxy-2-[L-1-3-(4-n-buthoxybenzoyl)propionyl)pyrrolidin-2-yl]acetate

In the same manner as in Example 20, a mixture of 3-(4-n-buthoxybenzoyl)propionic acid (1.73 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-n-buthoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate.

NMR(CDCl₃)δ: 0.98 (3H, t, J=8 Hz), 1.27 (3H, t, J=7 Hz), 1.43-1.57 (2H, m), 1.73-2.17 (6H, m), 2.60-2.86 (2H, m), 3.13-3.73 (4H, m), 4.02 (2H, t, J=7 Hz), 4.10-4.30 (2H, m), 4.36-4.46 (2H, m), 4.65-4.63 (1H, m), 6.88-6.94 (2H, m), 7.94-8.00 (2H, m)

EXAMPLE 34 Preparation of ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acetate

In the same manner as in Example 20, a mixture of 3-(4-t-butylbenzoyl)propionic acid (1.21 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acetate.

NMR(CDCl₃)δ: 1.23-1.34 (12H, m), 1.82-2.09 (4H, m), 2.60-2.88 (2H, m), 3.22-3.70 (4H, m), 4.10-4.42 (4H, m), 4.65-4.68 (1H, m) 7.46-7.49(2H, m), 7.93-7.96 (2H, m)

EXAMPLE 35 Preparation of ethyl (R,S)-2-hydroxy-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate

In the same manner as in Example 20, a mixture of 3-(2,5-dimethoxybenzoyl)propionic acid (1.23 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate.

NMR(CDCl₃)δ: 1.26-1.32 (3H, m), 1.80-2.15 (4H, m), 2.56-2.83 (2H, m), 3.26-3.72 (4H, m), 3.79 (3H, s), 3.88 (3H, s), 4.11-4.30 (2H, m),4.37-4.50 (2H, m), 4.65-4.69 (1H, m), 7.00-7.05 (2H, m), 7.30-7.32 (1H, m)

EXAMPLE 36 Preparation of ethyl 2-oxo-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}acetate (0.30 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl₃)δ: 1.38 (3H, t, J=7 Hz), 1.90-2.07 (3H, m), 3.67-3.73 (2H, m), 3.84 (3H, s), 4.35 (2H, q, J=7 Hz), 5.24 (1H, t, J=8 Hz), 6.90 (2H, d, J=9 Hz), 7.56 (2H, d, J=9 Hz)

EXAMPLE 37 Preparation of ethyl 2-oxo-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate (0.33g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl₃)δ: 1.39 (3H, t, J=7 Hz), 1.96-2.16 (2H, m), 2.31-2.40 (1H, m), 3.70-3.80 (2H, m), 3.89 (3H, s), 2.94 (3H, s), 4.34 (2H, q, J=7 Hz), 5.23-5.30 (1H, m), 6.85 (1H, d, J=8 Hz), 7.10-7.20 (2H, m)

EXAMPLE 38 Preparation of ethyl 2-oxo-2-{L-1-(4-methylbenzoyl)-pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S-2-hydroxy-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate (0.29 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl₃)δ: 1.39 (3H, t, J=7 Hz), 1.95-2.15 (3H, m), 2.35-2.42 (1H, m), 2.38 (3H, s), 3.60-3.76 (2H, m), 4.35 (2H, q, J=7 Hz), 5.21-5.2 (1H, m), 7.18-7.22 (2H, m), 7.45-7.48 (2H, m)

EXAMPLE 39 Preparation of ethyl 2-oxo-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate was oxidized to ethyl 2-oxo-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl₃)δ: 1.40 (3H, t, J=7 Hz), 1.90-2.03 (3H, m), 2.30-2.40(1H, m), 3.37-3.57 (2H, m), 3.88 (3H, s), 3.89 (3H, s), 3.91 (3H, s) 4.37 (2H, q, J=7 Hz), 5.23-5.29 (1H, m), 6.68 (1H, d, J=9 Hz), 7.02 (1H, d, J=9Hz)

EXAMPLE 40 Preparation of ethyl 2-oxo-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate (0.29 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl₃)δ: 1.39 (3H, t, J=7 Hz), 1.95-2.15 (3H, m) 2.35-2.45 (1H, m), 3.58-3.75 (2H, m), 4.37 (2H, t, J=7 Hz), 5.23-5.28 (1H, m), 7.06-7.13 (2H, m), 7.56-7.61 (2H, m)

EXAMPLE 41 Preparation of ethyl 2-oxo-2-[L-1-{3-(4-n-buthoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-n-buthoxybenzoyl)propionyl} pyrrolidin-2-yl}acetate was oxidized to ethyl 2-oxo-2-[L-1-{3-(4-n-buthoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl₃)δ: 0.98 (3H, t, J=7 Hz), 1.35 (3H, t, J=7 Hz), 1.50 (2H, q, J=7 Hz), 1.73-1.84 (2H, m), 1.98-2.23 (2H, m), 2.28-2.33 (2H, m), 2.61-2.88 (2H, m), 3.14-3.25 (1H, m), 3.44-3.46 (1H, m), 3.73 (2H, t, J=7 Hz), 4.02 (2H, t, J=7 Hz), 4.32 (2H, q, J=7 Hz), 5.04-5.10 (1H, m), 6.88-6.93 (2H, m), 7.93-7.96 (2H, m)

EXAMPLE 42 Preparation of ethyl 2-oxo-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acetate (0.35 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl₃)δ: 1.22-1.43 (12H, m), 1.98-2.33 (4H, m), 2.62-2.88 (2H, m), 3.17-3.28 (1H, m), 3.37-3.50 (1H, m), 3.71-3.76 (2H, m), 4.31 (2H, q, J=7 Hz), 5.04-5.09 (1H, m), 7.44-7.48 (2H, m), 7.90-7.95 (2H, m)

EXAMPLE 43 Preparation of ethyl 2-oxo-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate was oxidized to ethyl 2-oxo-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate byoxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl₃)δ: 1.35 (3H, t, J=7 Hz), 1.98-2.33 (4H, m), 2.55-2.85 (2H, m), 3.23-3.50 (4H, m), 3.78 (3H, s), 3.85 (3H, s), 4.32 (2H, q, J=7 Hz), 5.05-5.10 (1H, m), 6.88-7.00 (1H, m), 7.01-7.04 (1H, m), 7.28-7.30 (1H, m)

EXAMPLE 44 Preparation of ethyl (R,S)-2-hydroxy-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 3-benzoylpropionic acid (0.88 g, 5.0 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.04 g, 5.0 mmol) which was prepared in Reference Example 10, WSC (0.96 g, 5.0 mmol), HOBt (0.67 g, 5.0 mmol), and triethylamine (1.25 g) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate.

NMR(CDCl₃)δ: 1.25-1.31 (3H, m), 1.83-2.15 (4H, m), 3.23-3.73 (4H, m), 4.17-4.47 (4H, m), 4.68 (1H, d, J=7 Hz), 7.43-7.60 (3H, m), 7.98-8.03 (2H, m)

EXAMPLE 45 Preparation of ethyl (R,S)-2-hydroxy-2-(L-1-benzoylpyrrolidin-2-yl)acetate

The tittle compound which was prepared in Example 19 was synthesized in thesame manner as in Example 20. Benzoic acid (0.61 g, 5.0 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.04 g, 5.0 mmol) which was prepared in Reference Example 10, WSC (0.96 g, 5.0 mmol), HOBt (0.67 g, 5.0 mmol), and triethylamine (1.25 g) was stirred for 2 hours at -10° C.˜-20° C. and over night at room temperature gave ethyl (R,S)-2-hydroxy-2-(L-1-benzoylpyrrolidin-2-yl)acetate.

EXAMPLE 46 Preparation of ethyl (R,S)-2-hydroxy-2{L-1-(4-hydroxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 4-hydroxybenzoic acid (0.95 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(4-hydroxybenzoyl)pyrrolidin-2-yl}acetate.

NMR(CDCl₃)δ: 1.25-1.34 (3H, m), 1.60-2.20 (4H, m), 3.53-3.72 (2H, m), 4.21-4.42 (3H, m), 4.60-4.80 (2H, m), 6.65-6.76 (2H, m), 7.31-7.40 (2H, m), 7.70-8.05 (1H, brs)

EXAMPLE 47 Preparation of ethyl (R,S)-2-hydroxy-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 4-benzyloxybenzoic acid (1.08 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10° C.˜-20° C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2yl}acetate.

NMR(CDCl₃)δ: 1.29 (3H, t, J=7 Hz), 1.58-2.11 (4H, m), 3.50-3.55 (2H, m), 4.25 (2H, q, J=7 Hz), 4.45 (1H, d, J=7 Hz), 4.60 (1H, t, J=8 Hz), 4.71 (1H, d, J=7 Hz), 5.10 (2H, s), 6.95-7.00 (2H, m), 7.30-7.54 (7H,m)

EXAMPLE 48 Preparation of ethyl 2-oxo-2-(L-1-benzoylpyrrolidin-2-yl)acetate

The tittle compound which was prepared in Example 18 was synthesized in thesame manner as in Example 23. Ethyl (R,S)-2-hydroxy-2-(L-1-benzoylpyrrolidin-2-yl)acetate (0.27 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-(L-1-benzoylpyrrolidin-2-yl)acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

EXAMPLE 49 Preparation of ethyl 2-oxo-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate (0.30 g, 0.9 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl₃)δ: 1.35 (3H, t, J=7 Hz), 1.99-2.34 (4H, m), 2.62-2.90(2H, m), 3.19-3.31 (1H, m), 3.40-3.52 (1H, m), 3.72-3.77 (2H, m), 4.32 (2H,q, J=7 Hz), 5.05-5.10 (1H, m), 7.42-7.58 (3H, m), 7.96-8.00 (2H, m)

EXAMPLE 50 Preparation of ethyl 2-oxo-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate (0.13 g, 0.34 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.10 g, 0.8 mmol), DMSO (0.14 g, 1.8 mmol), and triethylamine (0.36 g, 3.6 mmol) in dichloromethane.

NMR(CDCl₃)δ: 1.38 (3H, t, J=7 Hz), 1.94-2.25 (4H, m), 3.67-3.82 (2H, m), 4.35 (2H, q, J=7 Hz), 5.10 (2H, s), 5.21-5.26 (1H, m), 6.96-7.05 (2H, m), 7.32-7.63 (7H, m) 

What is claimed is:
 1. A compound of the formula ##STR71## wherein R¹ is C₆ H₅ CH₂ ##STR72## R⁷ is hydrogen, lower alkyl, benzyl, ##STR73## n is an integer from 0 to 4; R²⁵ is --OH, --SH, --NH₂, --SCH₃, ##STR74## 4-imidazolyl, 3-indolyl or --CO2R²⁶ ; R²⁶ is hydrogen, lower alkyl or benzoyl; R⁸ is hydrogen or, when R⁸ and R⁷ are taken together with the adjacent nitrogen atom and carbon atom to which they are attached, they represent pyrrolidine; ##STR75## R¹¹ is hydrogen, lower alkyl, ##STR76## and R³⁰ and R³¹ are each independently hydrogen, halogen, lower alkyl or lower alkoxy.
 2. A compound according to claim 1, wherein R¹ is ##STR77## R⁷ is hydrogen, lower alkyl or benzyl, R⁸ is hydrogen or, when R⁸ and R⁷ are taken together with the adjacent nitrogen atom and carbon atom to which they are attached, they represent pyrrolidine and R¹¹ is lower alkyl.
 3. A compound of the formula: ##STR78## wherein R¹ is ##STR79## ##STR80## R³, R⁴ and R⁵ are each independently hydrogen, hydroxy, halogen, C₁₋₄ alkyl, phenyl unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, --O--R¹⁵, NH₂, --NHR¹⁷ and, N--R¹⁸ --R¹⁹, wherein R¹⁵ is phenyl; R¹⁷ is C₁₋₄ alkyl; R¹⁸ and R¹⁹ are each independently C₁₋₄ alkyl, benzyl, R⁶ is hydrogen or lower alkyl, R⁷ is hydrogen, lower alkyl, benzyl, ##STR81## or --(CH₂)_(n) --R²⁵ in which n is an integer of 0 to 4 and R²⁵ is --OH, --SH, --NH₂, --SCH₃, ##STR82## --CONH₂, ##STR83## 4-imidazolyl, 3-indolyl, or --CO₂ R²⁶, in which R²⁶ is hydrogen or C₁₋₄ alkyl; R⁸ is hydrogen or, when R⁸ and R⁷ are taken together with the adjacent nitrogen atom and carbon atom to which they are attached, they represent pyrrolidine; R⁹ is hydrogen, C₁₋₄ alkyl or phenyl; R¹⁰ is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or halogen; m is an integer of 0 to 3; R¹¹ is hydrogen, C₁₋₄ alkyl, phenyl, or ##STR84## R¹² is lower alkyl or, when R¹² and R¹² are each taken together, they represent lower alkylene; R¹³ is lower alkyl, phenyl, or benzyl.
 4. A compound of the formula: ##STR85## wherein R¹ is ##STR86## R³, R⁴, and R⁵ are each independently hydrogen, lower alkyl, lower alkoxy, halogen or phenyl; R⁶ is hydrogen or lower alkyl; R⁹ is hydrogen, lower alkyl, ##STR87## R³² is hydrogen, halogen, lower alkyl or lower alkoxy; R¹⁰ is hydrogen, halogen, lower alkyl or lower alkoxy; m is an integer of 0 to 3; R¹¹ is lower alkyl.
 5. A compound of the formula: ##STR88## wherein R¹ is ##STR89## R⁷ is hydrogen, lower alkyl or benzyl; R⁸ is hydrogen or, when R⁸ and R⁷ are taken together with the adjacent nitrogen atom and carbon atom to which they are attached, they represent pyrrolidine; R¹¹ is lower alkyl.
 6. A compound of the formula: ##STR90## wherein R¹ is C₆ H₅ CH₂ ##STR91## R¹¹ is lower alkyl.
 7. A compound of the formula: ##STR92## wherein R¹ is ##STR93## R² is ##STR94## R³, R⁴ and R⁵ are each independently hydrogen, lower alkyl, lower alkoxy or halogen; R¹¹ is lower alkyl.
 8. A compound of the formula: ##STR95## wherein R¹ is ##STR96## R³, R⁴ and R⁵ are each independently hydrogen, lower alkyl, lower alkoxy or halogen; m is an integer 0 to 3; R⁶ is hydrogen or lower alkyl; R⁹ is hydrogen, lower alkyl, ##STR97## R³² is hydrogen, halogen, lower alkyl or lower alkoxy; R¹⁰ is hydrogen, lower alkyl, lower alkoxy or halogen; R⁷ is hydrogen, lower alkyl or benzyl; R⁸ is hydrogen or, when R⁸ and R⁷ are taken together with adjacent nitrogen atom and carbon atom to which they are attached they represent pyrrolidine; R¹³ is methyl or ethyl.
 9. A compound of the formula: ##STR98## wherein R¹ is ##STR99## R² is ##STR100## R³, R⁴ and R⁵ are each independently hydrogen, lower alkyl, lower alkoxy or halogen; R¹¹ is lower alkyl.
 10. A compound of the formula: ##STR101## wherein R¹ is ##STR102## R⁹ is hydrogen, lower alkyl, ##STR103## R³² is hydrogen, halogen, lower alkyl or lower alkoxy; R¹⁰ is hydrogen, lower alkyl, lower alkoxy or halogen; m is an integer from 0 to 3; R¹¹ is lower alkyl.
 11. An anti-amnestic composition comprising a antiamnestically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
 12. A method of treating a patient suffering from, amnesia, comprising administering to the patient a daily dosage of 1 mg to 100 mg/kg of body weight of a compound according to claim 1 one or several times by oral administration or intravenous injection. 